Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats

U. Zumsteg, J. I. Reimers, F. Pociot, L. Mørch, S. Helqvist, M. Brendel, Rodolfo Alejandro, T. Mandrup-Poulsen, C. A. Dinarello, J. Nerup

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The monokines interleukin-1 α and -β have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1 β, and on interleukin-1 β induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1 β on mouse and rat thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100-1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1 βon rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1 β-induced inhibition of insulin release after 24 h. In contrast, interleukin-1 β-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1 β stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1 β effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist. An anti-mouse interleukin-1 receptor type I antibody completely abolished interleukin-1 β effects on isolated mouse islets. A 10-100-fold molar excess of interleukin-1 receptor antagonist antagonised interleukin-1 β-induced fever, hypercorticosteronaemia and hyperglucagonaemia, but not interleukin-1 β-induced reduction in insulin/glucose ratio in normal rats. In conclusion, our results suggest that antagonism of interleukin-1 β effects on beta cells requires higher concentrations of interleukin-1 receptor antagonist than those necessary to block interleukin-1 action on islet alpha cells and other interleukin-1 targets in vitro and in vivo. This may contribute to the understanding of the specificity of the immunological beta-cell destruction leading to insulin-dependent diabetes.

Original languageEnglish
Pages (from-to)759-766
Number of pages8
JournalDiabetologia
Volume36
Issue number8
DOIs
StatePublished - Aug 1 1993

Fingerprint

Glucagon-Secreting Cells
Interleukin-1 Receptors
Insulin-Secreting Cells
Interleukin-1
Rodentia
Insulin
Glucagon
Interleukin-1 Type I Receptors
Monokines
Inbred WKY Rats

Keywords

  • Cytokine
  • insulin-dependent diabetes mellitus
  • interleukin-1 receptor antagonist

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Zumsteg, U., Reimers, J. I., Pociot, F., Mørch, L., Helqvist, S., Brendel, M., ... Nerup, J. (1993). Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats. Diabetologia, 36(8), 759-766. https://doi.org/10.1007/BF00401148

Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats. / Zumsteg, U.; Reimers, J. I.; Pociot, F.; Mørch, L.; Helqvist, S.; Brendel, M.; Alejandro, Rodolfo; Mandrup-Poulsen, T.; Dinarello, C. A.; Nerup, J.

In: Diabetologia, Vol. 36, No. 8, 01.08.1993, p. 759-766.

Research output: Contribution to journalArticle

Zumsteg, U, Reimers, JI, Pociot, F, Mørch, L, Helqvist, S, Brendel, M, Alejandro, R, Mandrup-Poulsen, T, Dinarello, CA & Nerup, J 1993, 'Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats', Diabetologia, vol. 36, no. 8, pp. 759-766. https://doi.org/10.1007/BF00401148
Zumsteg, U. ; Reimers, J. I. ; Pociot, F. ; Mørch, L. ; Helqvist, S. ; Brendel, M. ; Alejandro, Rodolfo ; Mandrup-Poulsen, T. ; Dinarello, C. A. ; Nerup, J. / Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats. In: Diabetologia. 1993 ; Vol. 36, No. 8. pp. 759-766.
@article{3f25f9eedd0b487b9ea49f248a5d10cf,
title = "Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats",
abstract = "The monokines interleukin-1 α and -β have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1 β, and on interleukin-1 β induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1 β on mouse and rat thymocytes with a 50{\%} inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100-1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1 βon rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1 β-induced inhibition of insulin release after 24 h. In contrast, interleukin-1 β-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1 β stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1 β effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist. An anti-mouse interleukin-1 receptor type I antibody completely abolished interleukin-1 β effects on isolated mouse islets. A 10-100-fold molar excess of interleukin-1 receptor antagonist antagonised interleukin-1 β-induced fever, hypercorticosteronaemia and hyperglucagonaemia, but not interleukin-1 β-induced reduction in insulin/glucose ratio in normal rats. In conclusion, our results suggest that antagonism of interleukin-1 β effects on beta cells requires higher concentrations of interleukin-1 receptor antagonist than those necessary to block interleukin-1 action on islet alpha cells and other interleukin-1 targets in vitro and in vivo. This may contribute to the understanding of the specificity of the immunological beta-cell destruction leading to insulin-dependent diabetes.",
keywords = "Cytokine, insulin-dependent diabetes mellitus, interleukin-1 receptor antagonist",
author = "U. Zumsteg and Reimers, {J. I.} and F. Pociot and L. M{\o}rch and S. Helqvist and M. Brendel and Rodolfo Alejandro and T. Mandrup-Poulsen and Dinarello, {C. A.} and J. Nerup",
year = "1993",
month = "8",
day = "1",
doi = "10.1007/BF00401148",
language = "English",
volume = "36",
pages = "759--766",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "8",

}

TY - JOUR

T1 - Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats

AU - Zumsteg, U.

AU - Reimers, J. I.

AU - Pociot, F.

AU - Mørch, L.

AU - Helqvist, S.

AU - Brendel, M.

AU - Alejandro, Rodolfo

AU - Mandrup-Poulsen, T.

AU - Dinarello, C. A.

AU - Nerup, J.

PY - 1993/8/1

Y1 - 1993/8/1

N2 - The monokines interleukin-1 α and -β have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1 β, and on interleukin-1 β induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1 β on mouse and rat thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100-1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1 βon rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1 β-induced inhibition of insulin release after 24 h. In contrast, interleukin-1 β-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1 β stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1 β effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist. An anti-mouse interleukin-1 receptor type I antibody completely abolished interleukin-1 β effects on isolated mouse islets. A 10-100-fold molar excess of interleukin-1 receptor antagonist antagonised interleukin-1 β-induced fever, hypercorticosteronaemia and hyperglucagonaemia, but not interleukin-1 β-induced reduction in insulin/glucose ratio in normal rats. In conclusion, our results suggest that antagonism of interleukin-1 β effects on beta cells requires higher concentrations of interleukin-1 receptor antagonist than those necessary to block interleukin-1 action on islet alpha cells and other interleukin-1 targets in vitro and in vivo. This may contribute to the understanding of the specificity of the immunological beta-cell destruction leading to insulin-dependent diabetes.

AB - The monokines interleukin-1 α and -β have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1 β, and on interleukin-1 β induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1 β on mouse and rat thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100-1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1 βon rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1 β-induced inhibition of insulin release after 24 h. In contrast, interleukin-1 β-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1 β stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1 β effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist. An anti-mouse interleukin-1 receptor type I antibody completely abolished interleukin-1 β effects on isolated mouse islets. A 10-100-fold molar excess of interleukin-1 receptor antagonist antagonised interleukin-1 β-induced fever, hypercorticosteronaemia and hyperglucagonaemia, but not interleukin-1 β-induced reduction in insulin/glucose ratio in normal rats. In conclusion, our results suggest that antagonism of interleukin-1 β effects on beta cells requires higher concentrations of interleukin-1 receptor antagonist than those necessary to block interleukin-1 action on islet alpha cells and other interleukin-1 targets in vitro and in vivo. This may contribute to the understanding of the specificity of the immunological beta-cell destruction leading to insulin-dependent diabetes.

KW - Cytokine

KW - insulin-dependent diabetes mellitus

KW - interleukin-1 receptor antagonist

UR - http://www.scopus.com/inward/record.url?scp=0027227773&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027227773&partnerID=8YFLogxK

U2 - 10.1007/BF00401148

DO - 10.1007/BF00401148

M3 - Article

C2 - 8405744

AN - SCOPUS:0027227773

VL - 36

SP - 759

EP - 766

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 8

ER -